This invention relates to pharmaceutical compositions containing tPA or thrombolytic variants thereof. Such thrombolytic proteins are described, e.g. in U.S. Pat. application Ser. No. 825,104, filed 31 Jan. 1986; U.S. Ser. No. 853,781, filed 18 Apr. 1986; U.S. Ser. No. 861,699, filed 9 May 1986; U.S. Ser. No. 882,051, filed 2 July 1986, and PCT/US87/00257, filed 30 Jan. 1987.
Human tPA is known to have low solubility in the standard pharmaceutically acceptable excipients, most of which provide solubilities of less than 1 mg/ml. Others do not provide appreciable solubilities (&gt;1 mg/ml) without an undesirable increase in ionic concentration.
That low solubility phenomenon has made compounding human tPA into efficacious pharmaceutical formulations problematic. See, e.g. U.S. Pat. No. 4,777,043 (Genentech), GB No. 2 176 702 and GB No. 2 176 703 (Wellcome) and EP No. 211 592 (SmithKline). The Genentech patent relates to formulations of tPA containing 0.02M to 1M arginine. We have found that creatinine also exhibits an appreciable solubilizing effect (&gt;1 mg/ml) on plasminogen activator proteins. Notably, however, both of those excipients exhibit low thrombolytic solubility (&lt;1 mg/ml) at excipient concentrations of 0.1M and less. The other applications relate to low pH formulations of tPA.
Relatively concentrated formulations, containing at least about 2.5 mg of protein/ml, are particularly desirable for bolus injection of thrombolytic proteins, and would therefore be especially appropriate for "second generation" tPA proteins such as .DELTA.FE-1X (discussed infra.).
One advantage of such "second generation" compounds is that they have longer in vivo half lives than human tPA and may accordingly be administered as an intravenous bolus injection. In contrast, human tPA, which has a much shorter half-life, is administered as a continuous infusion over an extended period of time. Consequently, second generation plasminogen activators may be administered more rapidly and easily. Those advantages are particularly significant when, as with thrombolytics, administration of the therapeutic is a matter of life and death.
Bolus injection is practicable only if sufficiently concentrated formulations of the active agent are available. Furthermore, concentrated formulations are desirable to minimize the volume to be administered, and hence the time required to perform the injection.
Low excipient concentration is also desirable in formulations for IV bolus injection. High excipient concentration may increase osmolarity and tonicity of the formulation. Hypertonic solutions are deleterious to red blood cells and may cause patient discomfort, thus they should be administered more slowly. See Avis et al. Pharmaceutical Dosage Forms: Parenteral Medications, Vol. I, 168ff (1984). Pharmaceutical formulations that are isoosmotic and isotonic with respect to blood are preferred for rapid administration.
New formulations of thrombolytic proteins are clearly desirable. Ideally, such formulations would permit compounding the therapeutic protein in relatively high concentration with low concentration of excipients, provide enhanced protein stability, enhance the bioavailability of the protein, reduce costs of compounding the protein and improve the ease of administration of the pharmaceutical formulation.